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Esterase-activatable dimeric HDAC inhibitor nanotherapeutics for enhanced lymphoma epigenetic therapy
Tongyu Li1, Wanchuan Zhuang2, Shufang Fan3
1Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China; Department of Hematology, The First Affiliated Hospital of Ningbo University, 59 Liuting Road, Ningbo, Zhejiang 315010, China.
Background:
Despite advances in lymphoma therapy, significant challenges persist including R-CHOP resistance and CAR-T toxicity. Hydroxamate-based histone deacetylase inhibitors (HDACi) like vorinostat (SAHA) offer epigenetic therapeutic potential but are limited by poor bioavailability and rapid clearance.
Methods:
To overcome these barriers, we rationally designed an esterase- activatable dimeric prodrug by conjugating two SAHA molecules via a glutaric acid linker (SAHA-cc-SAHA). This prodrug co-assembled with DSPE-PEG2000 into nanoparticles (cc-diSAHA NPs). The system was characterized (DLS/TEM), and its drug release profile was assessed with/without porcine liver esterase (PLE). Antitumor activity was evaluated in EL4/A20 lymphoma cells (apoptosis/cycle assays, etc) and EL4 allograft. Transcriptomic mechanisms were deciphered by RNA-seq.
Results:
The cc-diSAHA NPs were uniform spheres (∼74 nm, PDI = 0.187) with excellent colloidal stability and minimal drug leakage (<4 % in 7 days), while enabling rapid drug release upon esterase stimulation (92.4 % within 7 h with PLE). In vitro, they demonstrated broad-spectrum anti-lymphoma activity, inducing G0/G1 arrest and apoptosis, albeit with delayed kinetics versus free formulations, consistent with a sustained-release profile. Transcriptomics revealed multifaceted mechanisms, including potent activation of interferon-mediated immunogenic stress and hematopoietic differentiation, alongside enriched adhesion and redox metabolism pathways. In vivo, intravenous cc-diSAHA NPs suppressed EL4 tumor growth significantly more than oral SAHA (819.36 vs 1594.40 mm³; p < 0.01), without inducing systemic toxicity or organ damage.
Conclusion:
This nanoplatform overcomes HDACi delivery barriers by reconciling the stability-activation paradox, providing a therapeutically viable option for lymphoma patients ineligible for standard intensive therapies.
Insights
This study developed novel nanoparticles for vorinostat (SAHA) delivery, improving lymphoma treatment by enhancing drug stability and release. The cc-diSAHA NPs showed significant tumor suppression and reduced toxicity in preclinical models.
Area of Science:
- Nanomedicine
- Epigenetics
- Oncology
Background:
- Lymphoma therapy faces challenges like R-CHOP resistance and CAR-T toxicity.
- Vorinostat (SAHA), a hydroxamate-based HDAC inhibitor, has therapeutic potential but suffers from poor bioavailability and rapid clearance.
- Existing treatments necessitate improved drug delivery systems for enhanced efficacy and reduced side effects.
Purpose of the Study:
- To design and characterize an esterase-activatable dimeric prodrug of SAHA (SAHA-cc-SAHA) formulated into nanoparticles (cc-diSAHA NPs).
- To evaluate the in vitro and in vivo antitumor activity and safety profile of cc-diSAHA NPs.
- To elucidate the underlying transcriptomic mechanisms of action for cc-diSAHA NPs in lymphoma.
Main Methods:
- Conjugation of two SAHA molecules via a glutaric acid linker and co-assembly with DSPE-PEG2000 into nanoparticles.
- Characterization of nanoparticle size, stability, and drug release kinetics in the presence of esterase.
- In vitro assessment of anti-lymphoma activity and cell cycle effects, and in vivo efficacy studies in EL4 xenografts.
- Transcriptomic analysis using RNA-seq to identify molecular mechanisms.
Main Results:
- cc-diSAHA NPs exhibited uniform size (~74 nm), excellent colloidal stability, and minimal drug leakage (<4% in 7 days).
- Rapid drug release was achieved upon esterase stimulation (92.4% within 7h with PLE), demonstrating controlled activation.
- In vitro studies showed broad-spectrum anti-lymphoma activity, inducing G0/G1 arrest and apoptosis.
- In vivo, cc-diSAHA NPs significantly suppressed EL4 tumor growth compared to oral SAHA (p<0.01) without systemic toxicity.
- Transcriptomics revealed activation of interferon-mediated immunogenic stress, hematopoietic differentiation, and altered adhesion/redox metabolism pathways.
Conclusions:
- The developed nanoplatform effectively overcomes delivery barriers for HDAC inhibitors like SAHA.
- cc-diSAHA NPs reconcile the stability-activation paradox, offering a promising therapeutic strategy for lymphoma.
- This approach provides a viable treatment option for lymphoma patients unsuitable for intensive standard therapies.
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